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Biologically active materials

a biological active material and material technology, applied in the field of biological active materials, can solve the problems of little selective concentration in tumour tissue, ubiquitous body distribution of drugs, and toxicity of parent drugs, and achieve the effect of reducing the degradation rate of dextrin

Inactive Publication Date: 2004-11-16
ML LAB PLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

It has now been surprisingly discovered that the rate of dextrin degradation is highly dependent on the degree of dextrin backbone substitution. As a result, it is possible to tailor the dextrin by appropriate substitution of its backbone in order to achieve a desired rate of degradation.
characterised in that said dextrin polymer is modified by the addition of pendent groups so that the stability of the polymer drug conjugate is enhanced.
It has been found that, in the case of substitution of the dextrin backbone by succinoylation, relatively rapid degradation takes place at a degree of succinoylation of up to about 15%. By contrast a degree of succinoylation above 30% very markedly reduces the rate of degradation.

Problems solved by technology

After intravenous (IV) administration, a large percentage of the injected dose leaves the circulation within a few minutes, resulting in a ubiquitous body distribution of drug and little selective concentration in tumour tissue.
However, these polymers have limitations.
For example, a dextran-doxorubicin conjugate has been tested clinically and been found to be much more toxic than the parent drug.
Furthermore the HPMA copolymers which have been clinically tested have the disadvantage of being non-biodegradable in the main chain.

Method used

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Examples

Experimental program
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Effect test

example 2

In this example the degradation of dextrins of different degrees of modification was compared. The results are shown in FIG. 1. It will be seen that native dextrin is rapidly degraded as are also dextrin with 5% succinoylation (whether with or without 6% Dox) and dextrin with 15% succinoylation. However, if dextrin is 34% succinoylated the degree of degradation is markedly less, there being zero % reduction of the peak mass of primary peak after 60 minutes and only 20% reduction after 180 minutes. In addition, FIG. 2 shows that 34% succinoylated dextrin doxorubicin conjugate is similarly stable over an extended time course when compared to unconjugated or low level succinoylated (5%) controls.

example 3

In this example increased uptake of 34% succinoylated dextrin-doxorubicin by tumour cells is shown. Male C57 were injected with 10.sup.6 B16F10 murine melanoma cells subcutaneously with either doxorubicin hydrochloride or dextrin-succinoyl-doxorubicin (34 mol % succinoylation, 11.8% doxorubicin) at 5 mg / kg doxorubicin equivalence into the intrapertinoneal cavity (i.p.).

The mice were then culled after 2, 5, and 30 mins and after 1, 2, 5, 24, and 48 hours. Tumours were removed and weighed. The tumour was then homogenised and doxorubicin extracted and quantified by HLPC for total doxorubicin present, FIG. 3.

FIG. 3 shows there is approximately a three fold increase in tumour levels of doxorubicin were found for the conjugate for all time intervals from 2 min up to 24 hours. After this period, there is no difference between conjugate or the free drug. The elevated levels of the conjugate were at their highest 5 min after injection.

example 4

In this example the pharmacology of succinolyated dextrin doxorubicin is determined and is presented in Table 2. Twenty four C57 black mice were injected subcutaneously (s.c.) with 10.sup.5 B16F10 murine melanoma cells as described above and then monitored daily for well-being and the presence of palpable tumours. When the tumours were palpable, mice were randomly assigned into groups of six and their tumours measured with a micrometer gauge. Tumour size and mouse body weight is recorded. Each group is then injected intra-peritoneally with either sterile saline (negative control), free doxorubicin (5 mg kg.sup.-1) in sterile saline or dextrin-doxorubicin (11.8 wt %, 34% succinolyation) at either 5 mg kg.sup.-1 or 10 mg kg.sup.-1, on days 0,1 and 2. The mice were monitored daily and tumour size and body weight recorded. Once the tumour area exceeded 2.89 cm.sup.2 the mice were culled according to UKCCCR guidelines. Mouse survival is then expressed as % T / C (test / control saline).

The a...

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Abstract

The present disclosure concerns biologically active materials, particularly materials that comprise a biodegradeable polymer linked to a biologically active agent. The disclosure further concerns materials known as polymer-drug conjugates that typically contain a therapeutic agent, for instance a bioactive cytotoxic drug linked to a polymer backbone. The linkage typically is a convalent linkage. However, in some embodiments the disclosure concerns other polymer conjugates including those where the biologically active agent is an imaging agent, such as a tyrosinamide, a diagnostic agent, or a targeting agent, such as biotin.

Description

This invention relates to biologically active materials and, in particular, to materials which comprise a biodegradable polymer linked to a biologically active agent. The invention is concerned with materials known as polymer-drug conjugates which typically contain a therapeutic agent for instance, a bioactive cytotoxic drug, linked to a polymer back-bone. The linkage between the polymer and the drug is typically by covalent bonding. However, the invention is applicable to other polymer conjugates including those where the biologically active agent is an imaging agent, such as tyrosinamide, a diagnostic agent, or a targeting agent such as biotin.Reference will be made hereinbelow to polymer-drug conjugates in which the drugs are anticancer agents. However, the present invention has application in connection with other drugs and / or bioactive agents.In designing a polymer-drug conjugate, the aim is to deliver a drug effectively to a therapeutic site such as a tumour. It is known, for ...

Claims

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Application Information

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IPC IPC(8): A61K47/48A61K51/06A61K51/02A61K31/704A61K45/00A61K51/00A61P35/00
CPCA61K51/065A61K47/4823A61K47/61A61P35/00
Inventor DUNCAN, RUTHHRECZUK-HIRST, DALEGERMAN, LISA
Owner ML LAB PLC
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